Marcia Zeigler

Identification of the gene causing mucolipidosis type IV.

Mucolipidosis type IV (MLIV) is an autosomal recessive, neurodegenerative, lysosomal storage disorder characterized by psychomotor retardation and ophthalmological abnormalities including corneal opacities, retinal degeneration and strabismus. Most patients reach a maximal developmental level of 12–15 months. The disease was classified as a mucolipidosis following observations by electron microscopy indicating the lysosomal storage of lipids together with water-soluble, granulated substances. Over 80% of the MLIV patients diagnosed are Ashkenazi Jews, including severely affected and mildly affected patients. The gene causing MLIV was previously mapped to human chromosome 19p13.2–13.3 in a region of approximately 1 cM (ref. 7). Haplotype analysis in the MLIV gene region of over 70 MLIV Ashkenazi chromosomes indicated the existence of two founder chromosomes among 95% of the Ashkenazi MLIV families: a major haplotype in 72% and a minor haplotype in 23% of the MLIV chromosomes (ref. 7, and G.B., unpublished data). The remaining 5% are distinct haplotypes found only in single patients. The basic metabolic defect causing the lysosomal storage in MLIV has not yet been identified. Thus, positional cloning was an alternative to identify the MLIV gene. We report here the identification of a new gene in this human chromosomal region in which MLIV-specific mutations were identified.

Mucolipidosis type IV: ganglioside sialidase deficiency.

Summary A solubilized sialidase is partially deficient in cultured fibroblasts derived from skin biopsies of four mucolipidosis IV patients. Fibroblasts from two obligate heterozygotes also have sialidase activity lower than normal controls. Membrane-bound sialidase activity is not affected in this disease. Based on previous and present findings, we propose that this solubilized activity is probably lysosomal origin. Sialidase activity in mucolipidosis IV cells is normal when neuraminlactose is used as substrate. Mixing cell homogenates from mucolipidosis IV patients and from controls results in the expected combined sialidase activity, indicating the absence of an internal inhibitor in the deficient cells. It is therefore suggested that the mutation in mucolipidosis IV specifically affects a lysosomal ganglioside sialidase, while the remaining non-lysosomal sialidases partially mask this deficiency.

Internalization of exogenous gangliosides in cultured skin fibroblasts for the diagnosis of mucolipidosis IV

The internalization of exogenous mixed brain gangliosides in ML IV cultured skin fibroblasts indicated an impairment of ganglioside catabolism in these cells. Incubation of ML IV, normal and various other lysosomal storage disorders cell lines for five days with exogenous tritium labelled GM3, GD1a or GT1 gangliosides allowed accurate quantitation of the retained gangliosides. This in vitro approach provides a reliable method for the diagnosis of ML IV.

Mucolipidosis type IV: the origin of the disease in the Ashkenazi Jewish population

Mucolipidosis type IV (MLIV) is a neurodegenerative lysosomal storage disease in which most of the patients diagnosed hitherto are Ashkenazi Jews. The basic metabolic defect causing this disease is still unknown and the relevant gene has not yet been mapped or cloned. Seventeen Israel Ashkenazi families with MLIV patients had been interviewed to study their family origin. Although the families immigrated to Israel from various European countries they all could trace their roots three to four generations back to northern Poland or the immediate neighbouring country, Lithuania. Furthermore, there are only one or two ultraorthodox families among the 70–80 Ashkenazi families with MLIV patients worldwide, a marked under-representation of this group which constitutes at least 10% of the Ashkenazi population. This data indicate that MLIV mutation occurred only around the 18th and 19th centuries, after the major expansion of this population, in a founder in this defined European region belonging to a more modern, secular family.

Hormonal environment and uterine response to epinephrine

Abstract The effect of epinephrine on rat myometrium pretreated with progesterone, estrogen, and propranolol was studied with the use of the isometric contraction technique. The results suggest a beta-receptor facilitation of progesterone that can be blocked by propranolol or estrogen, thus lending further support to the theory that the response of myometrium to catecholamines is dependent on the pre-existing hormonal environment.

Biochemical investigations of cultured amniotic fluid cells in mucolipidosis type IV

Biochemical abnormalities similar to those observed in cultured fibroblasts of patients with mucolipidosis type IV were demonstrated in cultured amniotic fluid cells of two fetuses affected with mucolipidosis IV. Increased gangliosides and acid mucopolysaccharides were observed in the affected cultures when compared to two normal controls. Both GM3 (monosialo) and GD3 (disialo) gangliosides accumulated in the affected cells: the latter showing a three-fold and the former a two-fold increase over controls. The major mucopolysaccharide components were dermatan sulfate and heparan sulfate, both increased approximately four-fold. A partial, but significant deficiency of soluble ganglioside sialidase was observed in the two affected cultures, while this activity was normal in a culture of a non-affected fetus of the same mother in a third pregnancy. Non-soluble membrane-bound and neuraminlactose sialidase was not affected.

The effect of Methergin on the lower urinary tract

SummaryThe effect of Methergin on the lower urinary tract musculature was studied in female cats using an isometric muscle contraction technique. Methergin had a direct stimulatory effect on the bladder wall and no apparent effect on urethral muscle. Contrary to current reports, Methergin showed alpha adrenergic blocking activity.